4,4'-Methylenedianiline, oligomeric reaction products with 1-chloro-2,3-epoxypropane

Endpoint summary

Description of key information

The acute toxicity of the substance is is low, the substance seems to be slowly absorbed by all routes and metabolized efficiently by epoxide hydrolases. The acute oral toxicity in rats (LD50) is greater 5000 mg/kg body weight, the acute dermal toxicity in rabbits is >3000 mg/kg body weight, and the acute inhalation toxicity in rats (LC50)was measured to be  >30 mg/m3 air (highest valour concentration to be achieved technically). 
At all routes of exposure  no signs of toxicity were recorded. Only during the oral test with a dose of 10'000 mg/kg body weight 1/2 animals died  without any adverse effects observed during necropsy.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP, but according to guideline OECD 401

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

other: limit test

Limit test:

yes

Species:

mouse

Strain:

other: Tif:MAG (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

4-5 week old mice, the mice were kept in groups of 2, in Macrolon cages type 2, with standarized soft wood bedding.
The animal room was air conditioned at 22 +/-3 °C, a relative humidity of 55 +/- 15%, a 12-hour light/dark cycle, and approximately 15 air changes per hour. Mouse standard food and water was supplied ad libitum.

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

-rior to dosing the animals were fasted over night.

Doses:

males and females were exposed to 5000 mg/kg body weight (single application)

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

Observation for mortality was on every day, mortality was checked daily, and body weight was determined on days 1, 7, 14, and at death

Statistics:

LD50 calculated including 95% confidence limits by the logit method (J. Berkson, J. Am. Stat. Ass. 39, 357 - 365 (1944)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

1/5 male mice died after 24 hours, no female mouse died at all (0/5)

Clinical signs:

other: sedation, dyspnoera, ruffeld fur, curved body position were the only symptoms observed, they disappeared on day 11 completely.

Gross pathology:

no gross pathological findings were recorded.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 in mice is > 5000 mg/kg body weight with only one dead male mouse.

Executive summary:

The oral LD50 in mice is > 5000 mg/kg body weight with only one dead male mouse.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP study performed without analytical measurements.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Vapour generated by an air-stream was passed through a inhalation chamber in which rats were exposed (whole body exposure) to the vapour stream for 4 hours. Observation was for 14 days post exposure.

GLP compliance:

no

Test type:

fixed concentration procedure

Limit test:

yes

Species:

rat

Strain:

other: Charles River albino rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

Younf male and female rats (average weight 209 gm) were checked for health before entering the test. Animals were housed individually , and food and water was supplied ad libitum.

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Exposure was in a 70l plexiglass chamber in which all rats were exposed by whole-body-exposure.
Cold air (-40°C) was passed through the test substance at a flow rate of 4.9 l/min, at a pressure of 29.92 inches of Hg at 25°C.
The average nominal vspour conc. was 30 mg/m3 air . This was the highest technically achievable concentration.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

>= 4 h

Concentrations:

30 mg/m3 air (average)

No. of animals per sex per dose:

5 ales and 5 females

Control animals:

yes

Statistics:

no statistics was applied

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 30 mg/m³ air (nominal)

Exp. duration:

4 h

Remarks on result:

other: whole body exposure

Mortality:

no mortality occurred during the exposure and during the 14-day observation period.

Clinical signs:

other: no substance-related clinical signs were recorded.

Body weight:

body weight development was equal to that of the air control group.

Gross pathology:

Compared to the control group, a slight discoloration of the liver of all treated animals was observed.

Other findings:

none

Interpretation of results:

relatively harmless

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

under the conditions of the test (30 mg/ MY720 per m3 air, for 4 hours) no signs of toxicity were recorded during the 14-day observation period.
The concentration used was the highest technically achievable concentration with this compound.
The LC50 is > 30 mg/m3 air as no mortality occurred and no adverse effects were noted.

Executive summary:

under the conditions of the test (30 mg/ MY720 per m3 air, for 4 hours) no signs of toxicity were recorded during the 14-day observation period. The concentration used was the highest technically achievable concentration with this compound. The LC50 is > 30 mg/m3 air as no mortality occurred and no adverse effects were noted.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

30 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no GLP, no guideline, as study is older than the guidelines

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Areas of the back of rabbits were shaved to comprise about 30% of the body surface., 24 hours prior to treatment . Test material was applied at different concentrations in a undiluted form. Semi-occlusive wrapping was performed for 24 hours , then the bandage was removed skin was washed and reactions were observed daily including mortality

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

All animals kept for 5 days under observation and clinical checks. Animals were housed on macrolon cages and fed standard laboratory diet (pellets) and water ad liobitum., except during a 16-hour period prior to treatment.
Initial and final body weights were recorded, moritalities and clinical signs.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

In order to prevent close contact og th mouthof the animals with the covered dermal site, each animal received a plastic collar to prevent such licking

Duration of exposure:

24 hours

Doses:

300, 1000 , 3000 mg/kg body weight

No. of animals per sex per dose:

1 male & 1 fmale rabbit each group

Control animals:

not required

Details on study design:

no data

Statistics:

no statistical analysis was performed

Preliminary study:

no RF-study performed

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Mortality:

300 mg/kg : 0/2
1000 mg/kg: 0/2
3000 mg/kg : 0/2

Clinical signs:

other: no clinical singns were recorded whicxh were treatment elated. At the end of the treatment period, local skin reactions were observed (slight erthema). At necropsy emaciation, pale kidney and pale liver were recorded in one high dose animal (male) which

Gross pathology:

no other gross pathological findings were recorded.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In this dermal toxicity test in rabbits the LD 50 was > 3000 mg/kg body weight

Executive summary:

In this dermal toxicity test in rabbits the LD 50 was > 3000 mg/kg body weight

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Additional information

The substance is of low acute toxicity by all three routes of exposure, oral, dermal and inhalation. Several acute oral and dermal toxicity studies in rats and rabbits show a similar result: up to 3000 mg/kg body weight no specific signs of toxicity were recorded, and no death occurred. Only at 10'000 mg/kg body weight 1/2 rats died most likely due to test substance effects. The only acute inhalation study was performed with a single dose of 30 mg/m3 air; the dose was chosen as it is the highest technically achievable vapour concentration. TGMDA is of low vapour pressure, and thus, higher dose levels are technically impossible, and to test as droplet aerosols (liquid) would give a completely different exposure scenario. Nevertheless, under the experimental conditions of 30 mg/kg body weight (whole body exposure) the animals showed no sings of toxicity, indicating that 30 mg/m3 air is far below the NOEC .

Justification for classification or non-classification

Based on the oral and dermal LD50 determined, no classification and labelling is required.

Concering the acute inhalation toxicity, the situation is slightly more complex. The dose of 30 mg/m3 air is far below the dose which would not require classification and labelling. However, due to the fact that this technically the highest achievable concentration in air of the substance (due to low vapour pressure and due to tha fact that no solid inhalable dust aerosol is possible , no higher concentrations could be tested. Using a droplet-aerosol would have caused a situation of no inhalation but oral uptake as these droplet would have been absorbed in the nasal cavity and transported to the upper part of the intestinal tract.